PROJECT SUMMARY/ABSTRACT: Obesity is a significant problem, with ~70% of the US population considered overweight or obese and estimated annual medical and economic costs >100 billion, yet there are few effective therapies currently available to combat obesity. The intake of appetizing high fat/high sugar foods has increased in parallel to the increased incidence of obesity, suggesting that targeting the pathways controlling the intake of these foods may be a viable mechanism for combating obesity. The mesolimbic dopamine system is the primary neural circuit controlling motivation and reward-related behavior, including the motivational and rewarding aspects of high fat/high sugar foods, and changes in dopamine circuits have been implicated in obesity. The melanocortin system is a neural circuit that plays in important role in controlling feeding and body weight, and it appears to interact with dopamine circuits to control feeding, in part through actions on MC3Rs in the ventral tegmental area (VTA). Overall, we have a poor understanding of how dopamine circuits control feeding however, including how melanocortin circuits and MC3Rs interact with dopamine circuits to control feeding and body weight. As both dopamine circuits and MC3Rs have been implicated in human obesity, these combined circuits may be an excellent target for potential future approaches to combat obesity. Therefore, increasing our currently limited understanding of how MC3Rs and VTA MC3R neurons interact with dopamine circuits to control feeding will greatly advance our ability to combat obesity. The central hypothesis of this proposal is that VTA MC3R neurons integrate information from multiple different neurotransmitters released from proopiomelanocortin (POMC) and agouti-related protein (AgRP) neurons to decrease feeding through the combined release of dopamine and glutamate in a restricted set of efferent target regions. This hypothesis will be tested in two specific aims. In Aim 1, advanced anatomical and electrophysiological approaches will be combined with in vivo optogenetics to test the hypothesis that POMC and AgRP neurons act in the VTA to control feeding and body weight by releasing multiple neurotransmitters that regulate the activity of VTA MC3R neurons. In Aim 2, anatomical approaches will be combined with in vivo optogenetics and DREADDs to test the hypothesis that VTA MC3R neurons directly control feeding through the combined release of dopamine and glutamate in specific efferent target regions. This project will significantly advance our understanding of the neural mechanisms controlling feeding and body weight and the development of obesity, and ultimately, this knowledge may allow for the identification of new strategies to treat and/or prevent obesity.